The removal of infectious agents by the host is fundamental for the survival of multicellular organisms. In animals and plants, the initial detection of microbial agents relies on specialized host receptors that recognize molecules expressed exclusively by microbes (Dang and Jones, Nature 411, 826–833 (2001); Medzhitov, Nature Rev. Immunol. 1, 135–145 (2001)). In animals, detection of microbial agents is mediated by the recognition of pathogen-associated molecular patterns (PAMPs) by specific host pattern-recognition receptors (PRRs) (Medzhitov, supra). Because the structure of each PAMP is highly conserved and invariant in microorganisms of the same class, the animal can recognize most or all microbes with a limited number of PRRs. The identification and characterization of plasma membrane Toll-like receptors (TLRs) as PRRs have provided fundamental insight into the mechanisms of host defense in animals. There is now compelling evidence that TLRs play a pivotal role in mediating immune responses to bacterial pathogens (Medzhitov, supra; Akira et al., Nat. Immunol. 2, 675–680 (2001)) In mammals, TLRs mediate host immune responses by inducing the secretion of several proinflammatory cytokines and co-stimulatory surface molecules through the activation of transcriptional factors including NF-κB (Medzhitov, supra; Akira et al., supra). The cellular response induced through TLR signaling mediates non-specific pathogen resistance as well as specific adaptive immunity, which leads to the removal of the invading pathogen. Other organisms, including nematodes and plants, have also developed unique strategies for the removal of microbial pathogens. For example, both nematodes and plants induce a suicide program in the infected cell that is important for pathogen removal (Aballay and Ausubel, Proc. Natl. Acad. Sci. U. S. A. 98, 2735–2739 (2001)). In the nematode, the suicide program is dependent on CED-4 and CED-3, which are also required for the elimination of damaged and unwanted cells (Liu and Hengartner, Ann N Y Acad Sci. 887, 92–104 (1999); Derry et al., Science 294, 591–595 (2001)). In plants, recognition of pathogens is mediated by disease resistance (R) genes that encode predicted membrane-bound and cytosolic proteins (Dang and Jones, supra). R proteins mediate the hypersensitivity response, which includes localized cell death at sites of pathogen invasion (Dang and Jones, supra).
Plants recognize distinct effector molecules from pathogenic bacteria through the cytosolic R proteins (Dang and Jones, supra). By contrast, most PRRs described in animals so far, including TLRs, recognize PAMPs in extracellular compartments or at the cell surface (Medzhitov, supra). Little is known about how the host cell can sense and respond to bacteria and other infectious microorganisms within the cell. Perhaps the best characterized system for intracellular recognition of pathogens is that mediated by double-stranded RNA (dsRNA), a PAMP produced by many viruses during their infection cycle (Williams, Oncogene 18, 6112–6120 (1999); Nanduri et al., EMBO J. 19, 5567–5574 (2000)). In response to viral infection, dsRNA activates PKR, a protein kinase that mediates a transcriptional host response against the virus (Nanduri et al., supra; Williams, supra). Experimental evidence for bacterial recognition in intracellular host compartments in animal cells is scarce. Nonetheless, recent studies in mammalian systems have revealed the presence of surveillance mechanisms to sense and respond to bacteria in the cytosol (Philpott et al., J. Immunol. 165, 903–914 (2000); O'Riordan et al., Proc. Natl. Acad. Sci. U S A 99, 13861–13866 (2002)). However, the host factors and signaling pathways involved in such recognition are still poorly understood and they are just beginning to emerge. Additional information on pathogen recognition and its relation to disease such as inflammatory disease are needed.